title: Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neurons.
abstract: Glucagon-like peptides (GLP-1/GLP-2) are coproduced and highlighted as key modulators to improve glucose homeostasis and insulin sensitivity after bariatric surgery. However, it is unknown if CNS GLP-2 plays any physiological role in the control of glucose homeostasis and insulin sensitivity. We show that mice lacking GLP-2 receptor (GLP-2R) in POMC neurons display glucose intolerance and hepatic insulin resistance. GLP-2R activation in POMC neurons is required for GLP-2 to enhance insulin-mediated suppression of hepatic glucose production (HGP) and gluconeogenesis. GLP-2 directly modulates excitability of POMC neurons in GLP-2R- and PI3K-dependent manners. GLP-2 initiates GLP-2R-p85α interaction and facilitates PI3K-Akt-dependent FoxO1 nuclear exclusion in POMC neurons. Central GLP-2 suppresses basal HGP and enhances insulin sensitivity, which are abolished in POMC-p110α KO mice. Thus, CNS GLP-2 plays a key physiological role in the control of HGP through activating PI3K-dependent modulation of membrane excitability and nuclear transcription of POMC neurons in the brain.
authors.affiliation: USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Shi
authors.forename: Fuguo
authors.initials: F
authors.lastname: Zhou
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Li
authors.forename: Benny
authors.initials: B
authors.lastname: Chang
authors.forename: Depei
authors.initials: D
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Tong
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Makoto
authors.initials: M
authors.lastname: Fukuda
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Zhao
authors.forename: Defa
authors.initials: D
authors.lastname: Li
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Burrin
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.forename: Xinfu
authors.initials: X
authors.lastname: Guan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D053767:Glucagon-Like Peptide 2 / Q000502:physiology*; D000067758:Glucagon-Like Peptide-2 Receptor; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D023421:Models, Animal; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D011333:Pro-Opiomelanocortin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D018027:Receptors, Glucagon / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D053767:Glucagon-Like Peptide 2; D000067758:Glucagon-Like Peptide-2 Receptor; D018027:Receptors, Glucagon; D011333:Pro-Opiomelanocortin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose